Improvements in hypertension and diabetes mellitus with osilodrostat in Cushing’s disease patients: Exploratory analyses from the Phase III LINC 3 study
R. Pivonello*a (Dr), M. Fleseriub (Dr), J. Newell-Pricec (Dr), A. Shimatsud (Dr), A. Lacroixe (Dr), RJ. Auchusf (Dr), A. Piacentinig (Mr), AM. Pedroncellih (Dr), BMK. Billeri (Dr)
a Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, ITALY ; b Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health & Science University, Portland, UNITED STATES ; c Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UNITED KINGDOM ; d Omi Medical Center, Kusatsu, JAPAN ; e Centre hospitalier de l’Université de Montréal, Montreal, CANADA ; f Division of Metabolism, Endocrinology and Diabetes, Departments of Internal Medicine and Pharmacology, University of Michigan, Ann Arbor, Ann Arbor, UNITED STATES ; g Recordati SpA, Milan, ITALY ; h Recordati AG, Basel, SWITZERLAND ; i Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital, Boston, UNITED STATES
Objectives: To explore changes in blood pressure and glucose homeostasis with osilodrostat therapy in Cushing’s disease patients with baseline hypertension and diabetes mellitus, respectively, during LINC 3 (NCT02180217).
Materials and methods: Adult patients with Cushing’s disease and with mean urinary free cortisol (mUFC) >1.5 times the upper limit of normal (ULN) received osilodrostat for 48 weeks. Baseline hypertension was defined as prior diagnosis, taking antihypertensive medication, and/or systolic blood pressure (SBP)/diastolic blood pressure (DBP) >130/>90 mmHg. Baseline diabetes mellitus was defined as prior diagnosis, taking antidiabetic medication, glycated haemoglobin (HbA1c) ≥6.5%, and/or fasting plasma glucose (FPG) ≥126 mg/dL.
Results: At baseline, 119/137 patients (87%) had hypertension; mean SBP/DBP decreased with osilodrostat therapy. Baseline SBP >130 mmHg (n=79) decreased to ≤130 mmHg at weeks 12, 24 and 48 in 58%, 51% and 49% of patients, respectively. Baseline DBP >90 mmHg (n=50) decreased to ≤90 mmHg at weeks 12, 24 and 48 in 72%, 62% and 66% of patients, respectively. SBP/DBP did not increase in patients without baseline hypertension. Of 85 patients receiving antihypertensives at baseline, an equal number (n=34 [40%]) stopped/reduced the dose and increased the dose/number of antihypertensives during the study. At baseline, 61/137 patients (45%) had diabetes mellitus. FPG decreased from ≥100 mg/dL at baseline (n=36) to <100 mg/dL by weeks 12, 24 and 48 in 58%, 64% and 44% of patients, respectively. More patients taking antihyperglycaemics at baseline stopped/reduced the dose (n=21/43 [49%]) than increased the dose/number of antihyperglycaemics during the study (n=10/43 [23%]). Neither changes in blood pressure nor in blood glucose parameters correlated with changes in UFC from baseline.
Conclusion: Consistent improvements in comorbid hypertension or diabetes mellitus occurred in many patients with Cushing’s disease during 48 weeks of osilodrostat treatment. Concomitant medication adjustments are required in some patients, including those with improvements in hypertension or diabetes mellitus.
The author has declared the following conflict(s) of interest:
MF reports grants to her university and occasional scientific consulting fees from Recordati Rare Diseases and Strongbridge and consulting fees from HRA Pharma and Sparrow; she served as a member of the LINC 3 steering committee. RP reports university grants and personal consulting fees from Novartis, Pfizer, HRA Pharma, Viropharma, Shire, and Ipsen, personal consulting fees from Ferring and Italfarmaco, and university grants from Corcept Therapeutics, Cortendo AB, and IBSA. JN-P reports research grants and consultancy payments to his university from Crinetics, Diurnal, HRA Pharma, Novartis, and Recordati Rare Diseases. AS reports serving as a member of the LINC 3 steering committee. AL reports grants and personal consulting fees from Novartis, Recordati, Corcept Therapeutics, Ipsen, and Novo Nordisk. RJA reports grants and personal fees from Spruce Biosciences, Neurocrine Biosciences, Corcept Therapeutics, and Novartis and personal fees from Janssen Pharmaceuticals, Crinetics Pharmaceuticals, OMass Therapeutics, Quest Diagnostics, Adrenas Therapeutics, and PhaseBio. AP and AMP are employees of Recordati. BMKB reports research grants to her institution from Novartis, Strongbridge, and Millendo and occasional consulting honoraria from HRA Pharma, Novartis, Recordati Rare Diseases, and Sparrow; she served on the LINC 3 steering committee.